FI73968C - Process for the preparation of phenylglycyl chloride hydrochlorides - Google Patents

Description

ADVERTISEMENT η τ nc Q ^ (11) UTLÄGGNINQSSKRIFT / o VO Ö c (45); v ~ ;; ru r (51) Kv.ik.4 / int.ci.4 C 07 c 101/04, 97/10, 87/28

SUOMI FINLAND

(FI) (21) Patent application - Patentansökning 801325 (22) Application date - Ansökningsdag 24.04.80

National Board of Patents and Registration (23) Start Date-Giltighetsdag 24.04.80

Patent-och registerstyrelsen (41) Has become public -Biiv offentiig 26.10.80 (44) Date of publication and of publication of the publication- 31. 08.87

Ansökan utlagd och utl.skriften oublicarad (86) Kv. Application-Int. ansökan (32) (33) (31) Privilege requested-Begärd priority 25.04.79 04.09.79, 04.09.79 Austrian Österreich (AT) A 3089/79, A 5852/79, A 5851/79 (71) Biochemie Gesellschaft mbH, Kundi, Tyrol, Austria-Austria (AT) (72) Gerd Ascher, Wörgl, Kurt Riedl, Kuistein, Austria-Austria (AT) (74) Oy Koister Ab (54) Method for the preparation of phenylglycyl chloride hydrochloride This invention relates to a process for the preparation of phenylglycyl chloride hydrochlorides of the formula

ft 'S — CH - COCl I

y 1 = J NH0-HCl R 2 wherein R is hydrogen or hydroxy, especially 4-hydroxy.

The compounds of formula I have an asymmetric carbon atom and may exist in racemic DL form, or in isomeric D or L form. The invention relates in particular to the preparation of D-isomeric forms, although the process is not limited to their preparation.

The compounds of formula I are known intermediates in the preparation of β-lactam antibiotics. For example, they can be reacted with 2,73968 with 6-aminopenicillanic acid (6-APA) of the formula

VN

λ- n -i-coOH

CT

or a salt or protected form thereof to give valuable penicillins of formula

(7S ~ ^ - CO - ΝΗη-B

R-NH2 O-N-Lc ° C H

wherein R is as defined above, or its salts or protected forms (which may be deprotected later or in situ). Their use as described above has been described in numerous publications. Of particular value are compounds in which R is hydrogen in the D-isomeric form or 4-hydroxy, since they can be combined in this way with well-known semisynthetic penicillins, such as ampicillin and amoxicillin.

They can also be reacted with 7-aminocephalosporanic acids or their derivatives of the formula / S \ η2νΊ-f I c

Cf-N sy ^ ~ CH2X

COOH

wherein X is hydrogen, acetoxy or another group present in known cephalosporin antibiotics, e.g. -SZ, wherein Z is a heterocyclic group, e.g. 1,2,3-triazol-5-yl, or salts thereof in protected forms, to give valuable cephalosporins of formula 3,73968

((7V-CH - CO - NH-T— {Sx D

m2

COOH

wherein R and X are as defined above, or their salts or protected forms (which may be deprotected later or in situ). Their use as described above has also been described in many publications. Even of particular value are the compounds of the formula I in which R is hydrogen in the D-isomeric form or 4-hydroxy, since they can be converted in this way, for example into well-known semisynthetic cephalosporin antibiotics such as cefalexin (R = H, X = H), cephaloglycine (R = H, X = acetoxy) or cefatricine (R * 4-OH, X = 1,2,3-triazol-5-yl).

The preparation of compounds of formula I, in particular those in which R is hydrogen, in particular 4-hydroxy, presents some difficulties. One generally known known method is described in Helv. Chim. Acta 39, 1525-1528 (1958) and proceeds according to the following reaction scheme: CHY - COOH COCl 2 CHY - CO 2 RC 1 CHY - COCl NH 2 dioxane ^ NH co ^ dioxane * NH 2 »HCl CO 2

E F G

(Ysn being a residue of any amino acid) This process for the preparation of D - (-) - 4-hydroxyphenyl-glycyl chloride hydrochloride is described in DE-A-2 364 192. The process is carried out under anhydrous conditions and excess phosgene is removed from the reaction mixture under Leuck anhydride F. after formation. The process uses the largest excess of gaseous hydrogen chloride. The same process applied to the preparation of D - (-) - 4-hydroxyphenylglycyl chloride hydrochloride 4,73968 chloride dioxane half solvate is described in DE-A-2 527 235.

There are some disadvantages associated with this known method.

These include, firstly, the difficulties involved in working with phosgene (which is highly toxic), secondly, the need to remove excess phosgene from the reaction mixture after formation of Leuck anhydride F (because this is unstable in the presence of phosgene), and thirdly, the relatively stringent conditions required ( preferably temperatures of 60 to 80 ° C to form intermediate F) and these tend to impair the yield and purity of the final product.

Also described previously, for example in GB Patent 1,241,844, is a process for the preparation of D - (-) - 4-hydroxyphenylglycyl chloride hydrochloride in which free glycine is reacted with phosphorus pentachloride followed by gaseous hydrogen chloride. However, as stated in DE-A-2 527 235, this process yields products whose physical properties are so poor that the process cannot be used in the large-scale production of penicillins and cephalosporins. In addition, the yields are very low.

With the method of the present invention, the above-mentioned disadvantages can be avoided.

The process according to the invention is characterized in that the compound of formula

^ ^ —CH - COOH II

Rx '- = / NH - COOR1 wherein R is hydrogen or hydroxy and R1 is straight or branched lower alkyl or bescyl is reacted with thionyl chloride in the presence of a strong acid and the resulting product is reacted with gaseous hydrogen chloride.

The term "lower alkyl" preferably means an alkyl group having 1 to 6, especially 1 to 4 carbon atoms. The alkyl group is preferably branched and is most preferably isopropyl.

5,73968

The first step of the process of the invention is suitably carried out under anhydrous conditions, and in an inert organic solvent such as a hydrocarbon, e.g. n-hexane, a chlorinated hydrocarbon such as methylene chloride, an ester or an ether, e.g. dioxane. This step is performed in the presence of a strong acid such as trichloroacetic acid, trifluoroacetic acid, p-toluenesulfonic acid or methanesulfonic acid.

The acid is preferably present in the most catalytic-equivalent amounts. Thionyl chloride is preferably added to a mixture of a compound of formula II, an inert solvent and a strong acid at a temperature of about 0 ° C. The reaction mixture can then be suitably maintained at a temperature between 30 ° C and the boiling point of the mixture until the reaction is complete. Typical reaction times range from about 1 to 4 hours.

The intermediate formed can be isolated from the reaction mixture and purified in a known manner. Alternatively, however, it can be used as such without further purification in the second step of the process. At this point, the intermediate or mixture containing the intermediate is suitably dissolved in an inert solvent, preferably an ether such as tetrahydrofuran, dioxane or a dialkyl ether, e.g. diethyl ether, diisopropyl ether or di-n-butyl ether, anisole, tetrahydrofuran or aromatic such as , to an ester such as butyl acetate or a chlorinated hydrocarbon such as methylene chloride.

Gaseous hydrogen chloride is then suitably introduced into this mixture. The step is suitably performed at a temperature between 0 ° C and room temperature. Hydrogen chloride is preferably introduced initially for a short time until the mixture is saturated, at a relatively low temperature, for example -5 to 10 ° C. The mixture can then, if desired, be treated with a seed crystal of the desired product. The HCl gas is then introduced into the mixture, preferably in a low flow at room temperature, for several hours, e.g. up to 15 hours.

The product formed can be isolated and purified in the usual way. When the reaction mixture in the second step of the process contains dioxane as a solvent or co-solvent, the product results in the formation of 6,73968 dioxane half solvates. However, if dioxane is not present and the solvent contains, for example, a dialkyl ether, tetrahydrofuran, anisole, aromatic hydrocarbon, ester or chlorinated hydrocarbon, the formation of a solvate-free product results. Preferred solvents for the preparation of the solvate-free product are dialkyl ethers, in particular diethyl, diisopropyl or di-n-butyl ether, tetrahydrofuran, anisole, esters, mainly butyl acetate, and chlorinated hydrocarbons, e.g. methylene chloride or mixtures thereof.

Relatively pure or crystalline, solvate-free D - (-) - 4-hydroxyphenylglycyl chloride hydrochloride is in fact believed to be a new product because, although this product is described in some way in DE-A-2 364 192, all of the processes specifically described therein use dioxane and dioxane half-solvate. Other known methods result in the formation of non-crystallized / impure products.

The process according to the invention is both new and surprising, in particular when used in connection with compounds of the formula I in which R is hydroxy, in particular 4-hydroxy, and in particular in connection with the compound D - (-) - 4-hydroxyphenylglycyl chloride hydrochloride. DE-A-2 364 192 states that processes for the preparation of acid glycid hydrochlorides of phenylglycine and substituted phenylglycines, including the use of thionyl chloride or phosphorus pentachloride, are known, but that these processes are unsatisfactory, at least for hydroxy-substituted phenyl. The fact that the process now described, which uses thionyl chloride in the first stage and HCl gas in the second stage, produces the final products in good yields and purity is therefore unexpected.

This method also has clear advantages over the above-mentioned phosgene method in that it avoids the use of phosgene, a highly toxic substance, and the substance does not have to be removed after the first step.

7,73968 This method is all the more surprising since it has been found that ε-osgene and thionyl chloride are not interchangeable, neither in the prior phosgene method nor in the method of the present invention. The previous method does not work when phosgene is replaced by thionyl chloride, and the method of this invention does not work if phosgene is used instead of thionyl chloride.

In fact, the process of this invention is believed to be different from the phosgene process in its mechanism and sequence of reactions. The exact nature of the intermediate involved in the process of the invention has not been elucidated, but the available values indicate that it is not the same as the Leuck anhydride formed in the phosgene process, at least when used to prepare compounds of formula I wherein R is hydroxy.

Some of the compounds of formula II used as starting materials, in particular those in which R1 is isopropyl, are novel compounds. Compounds of formula II may be prepared, for example, by carrying out a formula

(/ V — CH - COOH III

a salt of a compound of formula k, wherein R is as defined above, to react with a compound of formula

X - CO - 0 - R1 IV

wherein R 1 is as defined above and X is a leaving group, e.g. chlorine, bromine, iodine, azido or tosyl.

The method can be carried out in a known manner, for example as described in the following examples.

The following examples, in which all temperatures are in degrees Celsius, illustrate the invention.

73968 8

Example 1 D - (-) - 4-hydroxyphenylglycyl chloride hydrochloride (dioxane half solvate) 25 g of D - (-) - N-isopropoxycarbonyl-4-hydroxyphenylglycine are suspended in 250 ml of methylene chloride and 16 g of trichloroacetic acid are added to the mixture. Under ice-cooling and stirring, 16 ml of thionyl chloride are added, and after 10 minutes the mixture is allowed to warm to room temperature and stirred for 2-3 hours, at which point the starting material is no longer detectable by thin-layer chromatography. After evaporation of the solvent, the residue is dissolved in 300 ml of alkyl acetate and the solution is shaken once with 150 ml of water and then with 100 ml of brine. After drying over Na2SO4, the mixture is evaporated to dryness and the residue is dissolved in 160 ml of dry dioxane and 80 ml of toluene. Gaseous HCl is bubbled into the mixture under ice-cooling until the saturation point is reached. After seeding and stirring at room temperature, crystallization begins soon. After stirring overnight, the crystals of the title compound are filtered off and identified by IR. Yield 28%.

Example 2 D - (-) - Phenylglycyl chloride hydrochloride (dioxane half solvate) 2.5 g of D - (-) - N-isopropoxyphenylglycine, 25 ml of methylene chloride, 0.8 g of trichloroacetic acid and 1.2 ml of thionyl chloride are reacted as described in Example 1. After a reaction time of 3 hours, the mixture is cooled, 5 ml of dioxane are added and HCl gas is introduced into the mixture until the saturation point is reached. After seeding, the mixture is stirred at room temperature for several hours and then the product is isolated. Yield 60%.

Example 3 D - (-) - 4-hydroxyphenylglycyl chloride hydrochloride (dioxane half solvate) 2.5 g of D - (-) - N-isopropoxycarbonyl-4-hydroxyphenylglycine, 0.8 g of trichloroacetic acid and 25 ml of n-hexane are stirred under ice-cooling 1, With 2 ml of thionyl chloride and 9,73968 the mixture is boiled for one hour. The mixture is evaporated to dryness on a rotary evaporator and the residue is dissolved in 16 no dioxane and 8 no toluene. After HCl, cooling, impregnation, seeding and stirring for several hours at room temperature, the product is filtered off, washed with dioxane / toluene (1: 1), then with a small amount of methylene chloride and dried. The product is identified by IRt and methyl ester formation (thin layer chromatography). Yield 27%.

Example 4 D- (-) - 4-hydroxyphenylglycyl chloride hydrochloride (dioxane half solvate) 12.5 g of D - (-) - N-isopropoxycarbonyl-4-hydroxyphenylglycine are suspended in 125 g of any methylene chloride and 4 g of trichloroacetic acid and 8 ml of thionyl are added. The mixture is heated to moderate boiling for five hours, stirred and protected from water, and then cooled to 5 °. 25 ml of dioxane are added and HCl gas is bubbled into the mixture for 30 minutes. After seeding, the mixture is stirred at room temperature until crystallization begins. HCl is then bubbled through the mixture as a weak gas stream for six hours. The title compound is filtered off as a filter purged with neutral gas, washed with a small amount of methylene chloride and dried over P 2 O 5. Yield 78%.

Example 5 D - (-) - 4-hydroxyphenylglycyl chloride hydrochloride (dioxane half solvate) 2.25 g of D - (-) - N-methoxycarbonyl-4-hydroxyphenylglycine are dissolved in 20 ml of dioxane and 0.02 g of trichloroacetic acid are added. After adding 0.8 ml of thionyl chloride in 5 ml of dioxane to the mixture, the mixture is stirred at 50 ° for four hours, protected from moisture. The mixture is then stirred with 8 ml of toluene, cooled to about 0 ° and treated with HCl gas for one hour. The condenser is removed and after seeding the mixture is stirred for several hours at room temperature. The precipitate is filtered off, washed with methylene chloride and dried. Yield 27%.

73968 10

Example 6 D - (-) - 4-hydroxyphenylglycyl chloride hydrochloride (dioxane half solvate) 2.25 g of D- (-) - N-methoxycarbonyl-4-hydroxyphenylglycine are suspended in 25 ml of methylene chloride, 0.8 ml of trichloroacetic acid are then added and then is added at room temperature, dropwise with stirring 1.4 ml of thionyl chloride. The mixture is heated to moderate boiling, protected from moisture and stirred for 4-5 hours. The mixture is cooled, stirred with 7 ml of dioxane and then treated with hydrogen chloride gas for 30 minutes. After seeding, the mixture is stirred at 20-25 ° until crystallization begins. HCl gas is then bubbled through the mixture in a gentle stream over several hours, and the product is filtered off under protection from moisture, washed with methylene chloride and dried in a desiccator over P 2 O 3 and silica gel. Yield 52%.

Example 7 D - (-) - 4-hydroxyphenylglycyl chloride hydrochloride (dioxane half solvate) 2.4 g of D - (-) - N-ethoxycarbonyl-4-hydroxyphenylglycine are reacted and the treatment is continued otherwise as in Example 6, but 0.8 g: 1.6 g of trichloroacetic acid are used instead of n. Yield 30%.

Example 8 D - (-) - 4-hydroxyphenylglycyl chloride hydrochloride (dioxane half solvate) 2.7 g of D - (-) - tert-butoxycarbonyl-4-hydroxyphenylglycine are reacted as described in Example 6. Yield 70%.

Example 9 D - (-) - 4-Hydroxyphenylglycyl chloride hydrochloride (dioxane half solvate) 3 g of D- <= <-benzyloxycarbonylamino-OC-4-hydroxyphenylacetic acid are dissolved in 20 ml of dioxane, 0.05 g of trichloroacetic acid are added and trichloroacetic acid is added. 8 ml of thionyl chloride and the mixture are kept for one hour at 50 °, protected from moisture and with magnetic stirring. After the addition of 8 ml of toluene, the mixture 11 7396 8 is cooled to -5 ° and dry HCl gas is introduced for one hour. After seeding, the mixture is stirred for four hours at room temperature, whereupon the title compound separates, is isolated and dried in a vacuum desiccator over P 2 O 4 and silica gel. Yield 56%.

Example 10 D - (-) - 4-Hydroxyphenylglycyl chloride hydrochloride 12.5 g of D - (-) - N-isopropoxycarbonyl-4-hydroxyphenylglycine are reacted in 125 ml of methylene chloride with 8 g of trichloroacetic acid and with 8 ml of thionyl chloride. At 40 ° for three hours. The mixture is cooled with ice water, 100 ml of diisopropyl ether are added and HCl gas is bubbled into the mixture for 1 1/2 hours. Stirring overnight at room temperature gives a well crystallized, solvate - free product. Yield 80%.

Example 11 D - (-) - 4-Hydroxyphenylglycyl chloride hydrochloride

The mixture obtained by reacting thionyl chloride with D - (-) - N-isopropoxycarbonyl-4-hydroxyphenylglycine as described in Example 10 is stirred with 100 ml of di-N-butyl ether and converted to the title compound by introducing HCl gas into the mixture. Yield 81%.

Example 12 D - (-) - 4-Hydroxyphenylglycyl chloride hydrochloride

In the same manner as described in Example 10, but using either 75 ml of anisole, 50 ml of tetrahydrofuran or 75 ml of diethyl ether instead of the 100 ml batch of diisopropyl ether used, the title compound is obtained. Yield: a) anisole: 47% b) tetrahydrofuran: 72% c) diethyl ether: 83%

Example 13 D - (-) - 4-Hydroxyphenylglycyl chloride hydrochloride

A mixture of 38 g of p-toluenesulfonic acid, 125 ml of methylene chloride and 15 ml of thionyl chloride is heated at reflux for 1-1 1/2 hours. 50 g of D - (-) - N-isopropoxycarbonyl-4-hydroxyphenylglycine and 30 ml of thionyl chloride 12,73968 are added and the mixture is heated under gentle boiling for two hours. After adding 200 ml of dry butyl acetate, HCl gas is introduced under cooling. The mixture is then stirred for 1 hour at 5 ° and the HCl is continued to run again (30 minutes). After stirring for a further 30 minutes at 15 °, and adding 400-500 ml of dry methylene chloride, the mixture is stirred for 15 hours at room temperature and the reaction product is filtered off with a sintered glass filter to protect it from moisture. After washing with methylene chloride, the product is dried at room temperature in a vacuum desiccator. Yield 85%.

Example 14 D - (-) - 4-Hydroxyphenylglycyl chloride hydrochloride (dioxane half solvate)

A mixture of 190 g of p-toluenesulfonic acid / water in 625 ml of methylene dichloride is stirred briefly with 119 g of thionyl chloride. 253 g of D - (-) - N-isopropoxycarbonyl-4-hydroxyphenylglycine and 238 g of thionyl chloride are added and the mixture is boiled for 2 1/2 to 3 hours, after which a clear solution is formed after a short time. The mixture is cooled to 0 ° and, after the addition of 500 ml of dioxane, about 170 g of HCl gas are introduced into the vessel under external cooling until the HCl content is 100 mg / ml. Finally, the mixture is stirred for 10 hours at room temperature and the precipitated product is filtered off, washed with dioxane / methylene chloride (1: 1) and methylene chloride and dried in vacuo for 24 hours. Yield 86%.

The following examples illustrate the preparation of starting materials of formula II.

(a) D - (-) - N-isopropoxycarbonyl-4-hydroxyphenylglycine 1. 40 g of D - (-) - 4-hydroxyphenylglycine are suspended in 320 ml of water and stirred at room temperature with a solution of 9.6 g of sodium hydroxide in 80 ml. in water. The result is a clear solution with a pH of 9.7. Simultaneously prepare two other solutions - 9.9 g of sodium hydroxide in 80 ml of water and 29.2 ml of isopropyl chloroformate in 50 ml of acetone - and add dropwise so that the pH remains between 9.5 and 9.7 and the temperature does not rise above 25 ° . The mixture is stirred for two hours at room temperature. The final pH is 9.6.

13 73968

The acetone is evaporated off and the aqueous solution is extracted once with 50 ml of ether and acidified with hydrochloric acid (1: 1), and the acylated product is extracted three times with a total of 250 ml of ethyl acetate. The purified extracts are dried and the ethyl acetate is evaporated off as much as possible. The residue is dissolved in chloroform while dissolving under heating, and the mixture is evaporated to remove ethyl acetate as completely as possible. The residue is dissolved in 150 ml of chloroform, reheated, and crystallization is completed by adding 60 ml of hexane. After drying, the melting point of the product is 163-164 °.

2. The procedure of Example ai is repeated until the acetone is evaporated. The resulting solution is filtered, mixed with 40 ml of concentrated ammonia or an equivalent amount of sodium hydroxide, and allowed to stand at room temperature for 1-2 hours. The mixture is then acidified with hydrochloric acid (1: 1) under cooling with slow stirring until the pH is 1.5 to 2 and seeded when turbidity appears. Stirring is continued until crystallization is complete. The product is identified by titration and IR.

3. Suspend 500 g of D - (-) - 4-hydroxyphenylglycine in 4 liters of water, cool the suspension to 2 to 5 ° and slowly add dropwise a solution of 360 g of sodium hydroxide per liter of water. The temperature is kept at 5 ° or below. 900 ml of isopropyl chloroformate are then added. The temperature is again maintained at 5 °. The mixture is stirred for 1 hour under ice-cooling and then 780 ml of 10-norm are added. NaOH. After 30 minutes at 20 °, the mixture is filtered, the filtrate is acidified with sulfuric acid until cloudy. After a crystallization time of 5-10 minutes, sulfuric acid is added with stirring until the pH has reached 2.0. To complete the crystallization, the mixture is stirred for 15-30 minutes under ice-cooling. The mixture is washed with water and dried in vacuo in an oven, first at 50 °, then at 80-90 °. The title compound thus obtained is pure by thin layer chromatographic analysis, has a melting point of 162-164 ° and a specific rotation capacity of Z'c? S_7jj = -155 (c * 1 in methanol).

14 73968 b) D - (-) - N-methoxycarbonyl-4-hydroxyphenylglycine

A mixture of 40 g of D - (-) - 4-hydroxyphenylglycine in 320 ml of water is mixed with a solution of 9.6 g of NaOH in 80 ml of water. To this is added dropwise, by cooling with water, a mixture of 9.6 g of NaOH in 80 ml of water and 19.8 ml of methyl chloroformate in 40 ml of acetone so as to maintain the pH between 9.5 and 9.8. In addition, 35 ml of 3-norm is required. NaOH. After stirring for two hours at room temperature, the final pH is 9.5. The acetone is evaporated off, the mixture is filtered and the aqueous phase is acidified with hydrochloric acid (1: 1) and extracted with ethyl acetate. The mixture is evaporated to dryness and the residue is recrystallized from chloroform / hexane to give the pure title compound. Sp. 134-137 °.

c) D - (-) - N-isopropoxycarbonylphenylglycine 113.1 g of D - (-) - phenylglycine are suspended in a liter of water and the pH is adjusted to between 10.2 and 10.4 by adding under cooling (ice-water) and stirring at 50%. NaOH. 225 ml of isopropyl chloroformate and 50% sodium hydroxide are added simultaneously so as to maintain the pH within said range. The reaction mixture is then basified to a pH of 12 to 13 and stirred at this pH for 40 minutes. Practically the clear solution is acidified with concentrated hydrochloric acid, cooling until cloudy. The mixture is seeded to initiate crystallization and after 20 minutes the pH is further dropped to 2.0. After a crystallization time of 30 minutes, the mixture is filtered and the residue is washed five times with 100 ml of water and dried in vacuo in an oven using silica gel at 50-60 °. After trituration, it is then further dried for 16 to 17 hours at 60 to 70 °. Sp. 116-120 ° (from ethyl acetate).

Other compounds of formula II used in the above examples may be obtained in the same manner as described in Examples a to c above.

Characterization of D - (-) - 4-hydroxyphenylglycyl chloride hydrochloride (dioxane half solvate): = “95 ° (C = 1, 1 NHC1)

Solvent content (gc) = dioxane 16%; C 1 H 2 O 2 0.2% 15 73968 IR peaks cm -1: 3280 (s); 1770 (s); 1735 (s); 1210 (s); 1170 (s); 865 (s).

Characterization of solvate-free crystalline D - (-) - hydroxyphenylglycyl chloride hydrochloride: = ”112 (c = 1, 1 NHCl)

Solvent content (gc) = butyl acetate 0.5%? Cl 2 Cl 2 0.2% IR peaks cm -1: 3000 (Br); 1735 (s)? 1170 (s); 830

The melting point could not be determined due to decomposition.

Claims (5)

16 73968 Process for the preparation of phenylglycyl chloride hydrochlorides of the formula y-CH - COCl (I) NH 2 .HCl wherein R is hydrogen or hydroxy, characterized in that the compound of the formula y-CH - COOH (II) NH - COOR 1 wherein R is the same as above and R 1 is straight-chain or branched lower alkyl or benzyl, is reacted with thionyl chloride in the presence of a strong acid and the product obtained is reacted with gaseous hydrogen chloride. Process according to Claim 1, characterized in that the strong acid is trichloroacetic acid or p-toluenesulfonic acid. Process according to Claim 1 or 2, characterized in that the reaction with gaseous hydrogen chloride is carried out in an inert dioxane-containing solvate, the product being obtained in the form of a dioxane half-solvate. Process according to Claim 1 or 2, characterized in that the reaction with gaseous hydrogen chloride is carried out in an inert solvent which does not contain dioxane, the product being obtained in solvate-free form. Process according to Claim 4, characterized in that the inert solvent is a dialkyl ether, tetrahydrofuran, anisole, an aromatic hydrocarbon, an ester or a chlorinated hydrocarbon.